Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Cerebral amyloid angiopathy (CAA) involves amyloid-beta accumulation in cerebrovasculature, compromising blood vessel integrity and accelerating cognitive decline in Alzheimer's Disease (AD).
• Previous genome-wide association studies (GWAS) linked a LINC-PINT splice variant to reduced CAA levels in non-APOEe4 individuals and increased LINC-PINT expression in AD brains.
• This research expands the GWAS cohort to include more AD and non-AD donors with CAA scores.

Purpose of the Study:

• To identify genetic variants associated with cerebral amyloid angiopathy (CAA) through an expanded genome-wide association study (GWAS).
• To investigate the role of the LINC-PINT splice variant in CAA, particularly in relation to APOEe4 status and AD.
• To explore the genetic architecture of CAA in both AD and non-AD individuals.

Main Methods:

• Expanded GWAS incorporating genetic data from 550 AD and 502 non-AD donors from the Mayo Clinic Brain Bank.
• Performed quality control and imputation (TOPMED) on all datasets.
• Conducted GWAS using linear regression, testing imputed variant dosages against CAA scores, with adjustments for covariates and interaction analyses with APOEe4 presence and sex.

Main Results:

• Variants at the APOE locus were the most significant findings.
• Several other variants approached genome-wide significance after adjusting for AD neuropathology (Braak stage, Thal phase).
• The LINC-PINT splice variant confirmed its association with lower CAA scores in AD donors lacking the APOEe4 allele.

Conclusions:

• The study provides further insights into the genetic underpinnings of CAA risk, relevant to both AD and non-AD contexts.
• Characterizing genetic variants and their functional consequences may reveal novel biomarkers and therapeutic strategies for CAA.
• CAA is a common comorbidity in individuals with and without AD, underscoring the importance of understanding its genetic basis.